Ertapenem sodium has the structure of formula I, which chemical name is (1R,5S,6S,8R,2S*,4S*)-2-[2-[(3-carboxyphenyl)carbamoyl]-pyrrolidinyl-4-thio]-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid monosodium salt. Ertapenem sodium is a novel broad-spectrum carbapenem antibiotic jointly developed by Merck & Co. (U.S.) and AstraZeneca, which has good antibacterial activities against gram-positive and gram-negative aerobic and anaerobic bacteria.

Polymorphism is an important nature of a compound, and is generally present in the majority of chemical drugs. Substance in different crystalline form has important influence on the stability, uniformity, bioavailability, and formulation, etc. Ertapenem sodium is poor in stability, and is highly sensitive to heat, acid, etc. In order to reduce the degredation of the product, and to improve the quality of formulation product, research workers have performed enormous studies on the crystalline forms of ertapenem sodium, and various crystalline forms of ertapenem sodium and the preparation methods therefor have been disclosed in the prior art.
For example, WO03026572 discloses crystalline form A and crystalline form B of ertapenem sodium and the preparation method therefor. The crystalline form A has major diffraction peaks at about 4.8°, 6.7°, 10.5°, 11.7°, 13.6°, 14.4°, 16.0°, 17.2°, 18.4°, 19.7°, 20.8°, 21.6°, 22.1°, 23.1°, 24.1°, 26.1°, 26.6°, 27.0°, 27.4°, 28.6°, and 31.1° in the X-ray diffraction spectrum presented by 2θ angle. The crystalline form B has major diffraction peaks at about 4.8°, 6.8°, 7.8°, 10.4°, 11.8°, 13.6°, 14.4°, 15.2°, 17.3°, 18.5°, 19.0°, 19.7°, 20.9°, 21.9°, 23.1°, 24.1°, 24.5°, 26.1°, 26.5°, 26.9°, 27.7°, 28.7°, 30.0°, 31.1°, and 32.2° in the X-ray diffraction spectrum presented by 2θ angle.
The method for preparing crystalline form A comprises: a) adding 1-propanol to an aqueous solution containing ertapenem of formula II and III and/or salt forms thereof; b) cooling the solution to below −5° C.; c) adjusting the pH to between about 6 and about 5 utilizing an acid; d) crystallizing by adding to the solution from about 0.5 to about 3 volumes of methanol relative to the aqueous solution volume, and from about 0.5 to about 3 volumes of 1-propanol relative to the aqueous solution volume; and e) isolating to obtain the crystalline form A of ertapenem sodium.

The method for preparing crystalline form B comprises the steps of: washing the crystalline form A of ertapenem sodium with a mixture of water and 2-propanol to give the crystalline form B, wherein said mixture contains about 5% to about 25% water (v/v).
In addition, WO03027067 discloses a crystalline form C of ertapenem sodium. In the method disclosed by this patent, the crystalline form C of ertapenem sodium is isolated and obtained after washing the above-mentioned crystalline form A or crystalline form B of ertapenem sodium with a aqueous solvent of ethyl acetate, acetone, or a mixture thereof. The crystalline form C of the compound has major diffraction peaks at about 4.8°, 6.8°, 7.8°, 10.7°, 11.8°, 13.7°, 14.6°, 17.3°, 18.6°, 19.14°, 19.9°, 21.0°, 22.1°, 24.2°, 26.1°, 27.9°, 28.7°, 31.3°, and 32.5° in the X-ray diffraction spectrum presented by 2θ angle.
The methods for preparing crystalline form A, crystalline form B, and crystalline form C of ertapenem sodium all have the following disadvantages: in the above-mentioned methods, when ertapenem sodium is crystalized, the concentrations for the crystalization solutions of ertapenem sodium are all required to be above 100 mg/ml. Due to the fact that ertapenem sodium is easily to be degraded and polymerized, conventional concentration and nanofiltration will cause substantive degradation of the product. Therefore, due to the excessive concentration of ertapenem sodium solution, both the purity and the chroma of the crystal are difficult to meet the requirements. In addition, large amount of solvent is also introduced in the above-mentioned method, which is not conducive to the environmental protection.
WO2009150630 discloses a crystalline form D of ertapenem sodium. This crystalline form D has major diffraction peaks at about 4.44°, 5.26°, 7.44°, 8.12°, 10.98°, 12.74°, 19.28°, 22.93°, 23.51°, 25.07°, and 30.15° in the X-ray diffraction spectrum presented by 2θ angle. The method for preparing crytalline form D comprises the following steps: a) treating ertapenem sodium with water and methanol; b) treating the solution obtained in step a) with 1-propanol; c) stirring the mixture obtained in step b) at a temperature of about 0° C. or below 0° C., for the precipitation of solid; d) treating the solid obtained in step c) with acetone, to obtain the crystalline form D of ertapenem sodium. The disadvantages of the crystalline form D of ertapenem sodium are that the crystallization properties are poor, the particle is small, and filtration by suction is difficult.
In addition to the above-mentioned various crystalline forms product of ertapenem sodium disclosed in the prior art, several methods for preparing amorphous products of ertapetanem sodium have also been disclosed in the prior art, for example:
In CN1752090A, acetone and propanol are added into a reaction system of ertapenem sodium after extraction, and insolubles are removed, and the product is precipated by means of evaporative crystallization, which is then washed by 95% ethanol and methyl acetate, and purified, to obtain an amorphous product of ertapenem sodium.
For another example, a method for preparing ertapenem sodium solid is recited in “Synthesis of carbapenem antibiotic ertapenem” by ZHANG Yi-feng (Journal of China Pharmaceutical University, 2007, 38(4): 305-310), which comprises the following steps: the reaction liquid of ertapenem sodium is filtered, then the filtrate is extracted with dichloromethane, and the aqueous layer is concentrated under reduced pressure to remove organic solvent, then purified by CHP-20P resin, and then lyophilized to obtain white powder of ertapenem sodium, which shows an amorphous product after examined by X-ray.
The main disadvantages of the above-mentioned amorphous product of ertapenem sodium are: poor stability, low purity, and that it is difficult for the color grade to meet the requirements.